The present invention includes methods and reagents for treatment of Systemic Lupus Erythematosus (xe2x80x9cSLExe2x80x9d) patients characterized double stranded (ds) DNA by administration of reagents reactive with doublestranded DNA antibodies to alleviate damage resulting from the antibodies.
The laboratory directed by Morris Reichlin at the Oklahoma Medical Research Foundation, Oklahoma City, Okla., has been engaged in the study of autoimmune responses to RNAprotein antigens in SLE patients for over 20 years. Researchers have reported the initial descriptions of the Ro/SSA (Clark, G. M., Reichlin, M. and Tomasi, T. B. J. Immunol., 102:117-122 (1969)), La/SSB (Mattioli, M. and Reichlin, M. Arthritis Rheum., 17:421-429 (1974)), and nRNP(U1RNP) (Mattioli, M. and Reichlin, M. J. Immunol., 107:1281-1290 (1971)) systems, while others described the Sm antigen (Tan, E. M. and Kunkel, H. G. J. Immunol., 99:464-471 (1966)).
Over time, it has become apparent that certain profiles of anti-RNA protein antibodies are positively correlated with nephritis while other profiles are xe2x80x9cnegativelyxe2x80x9d correlated or xe2x80x9cprotectedxe2x80x9d from the development of serious renal disease. Thus, antibodies to nRNP(U1RNP) alone were found to have a low frequency of nephritis (Sharp, G. C., et al. Am. J. Med., 52:148-159 (1972); Reichlin, M. and Mattioli, M. N. Engl. J. Med., 286:908-911 (1972)) while patients with both anti-nRNP and anti-Sm (or anti-Sm alone) had a high frequency of nephritis (Reichlin, M. and Mattioli, M. N. Engl. J. Med., 286:908-911 (1972); Maddison, P. J., et al. J. Rheumatol., 5:407-411 (1978)). In patients with anti-Ro/SSA alone, a high frequency of nephritis was noted (Wasicek, C. A. and Reichlin, M. J. Clin. Invest., 69:835-843 (1982); Hamilton, R. G., et al., Arthritis Rheum., 31:496-505 (1988); Harley, J. B., et al. Arthritis Rheum., 32(7):826-836 (1989)), while in those with both anti-Ro/SSA and anti-La/SSB, a low prevalence of nephritis was found. Studies of acid eluates from lupus nephritis kidneys have demonstrated enrichment of anti-Ro/SSA compared to serum levels (Maddison, P. J. and Reichlin, M. Arthritis Rheum., 22:858-863 (1979)), supporting the participation of Ro/SSA-anti-Ro/SSA complexes in the development and/or the perpetuation of the nephritis. Elution studies of antibodies to the U1RNP/Sm complex also showed enrichment, but the precise specificities of these complexes (anti-Sm or anti-nRNP) were not determined because of technical limitations (Koffler, et al. J. Exp. Med., 134:294-312 (1971)). Serum levels of anti-Sm antibodies have been shown to fluctuate with disease activity (including nephritis) in some SLE patients (Barada, et al., Arthritis Rheum., 24:1236-1244 (1981)). These data indicate a role for the Ro/SSA and Sm systems in the development of nephritis, but only 50% of patients with either anti-Ro/SSA alone or anti-nRNP and anti-Sm (or anti-Sm alone) develop nephritis.
Much data support a major role for the DNA-anti-DNA system in the pathogenesis of lupus nephritis. Clinical studies show that high serum anti-DNA levels correlate positively with the activity of nephritis, and that remissions are associated with declining anti-DNA levels (Harley, et al., Arthritis Rheum. (1989); Tan, et al. J. Clin Invest., 45:1732-1740 (1966); Schur, P. H. and Sandson, J. N. Engl. J. Med., 278:533-538 (1982)). Anti-DNA has been shown to be enriched in serum cryoglobulins (Winfield, et al., J. Clin. Invest., 56:563-570 (1975)) and in acid eluates of lupus nephritis kidneys (Maddison and Reichlin (1979); Miniter, et al., Arthritis Rheum., 22:959-968 (1979); Beaulieu, et al. Arthritis Rheum., 22:565-570 (1979)). In all these studies, the specificity of these antibodies are to dsDNA (double stranded or native DNA).
Antibodies to native or ds DNA play a special role in the clinical diagnosis and pathology of Systemic Lupus Erythematosus (SLE). These autoantibodies are highly specific, frequently correlate positively with disease activity (especially nephritis), and remissions are usually associated with declining anti-dsDNA levels (Hahn and Tsao, Antibodies to DNA. -Tn Dubois, Systemic Lupus Erythematosus. D- J. Wallace and B. H. Hahn, editors. (Lea and Febiger, Philadelphia, Pa. 1993) pp. 195-201; Harley, et al., Arthritis Rheum. 32:826-836 (1989); Tan, et al., J. Clin. Invest. 45:1732-1740 (1966); Schur and Sandson, N. Engl. T. Med. 278:533-538 (1982)). Patients who produce antibodies to the Ro/SSA and La/SSB (Harley, et al. (1989); Wasicek and Reichlin, J. Clin. Invest. 69:835-843 (1982); Hamilton, et al., Arthritis Rheum. 31:496-505 (1988); antigens as well as those that only have precipitins to U1RNP (Sharp, Am. J. Med. 52:148-159 (1972); Reichlin and Mattioli, N. Engl. J. Med. 86:908-911 (1972)) very infrequently have anti-dsDNA in their serum and have a correspondingly low prevalence of nephritis. The mechanisms of these negative relationships of antibodies to Ro/SSA and La/SSB and U1RNP with anti-dsDNA are not understood.
Studies have been reported in the literature describing differences in the ability of murine monoclonal antibodies to dsDNA to induce nephritis when hybridomas producing these antibodies are placed in normal mice (Tsao, et al. J. Clin. Invest., 85:530-540 (1990)). Others have shown that murine monoclonal antibodies penetrate cells, bind to nuclei, and induce glomerular proliferation and proteinuria in vivo (Vlahakos, et al., J. Am. Soc. Nephrol. 2:1345-1354 (1992)). Most recently, others have reported direct in vitro binding of murine monoclonal antibodies to glomeruli which is DNA dependent (DiValerio, et al., Clin. Res., 42:139A (1994)).
Reichlin, et al., The Immunologist 3/3, 84-88 (1995), characterizes anti-dsDNA antibodies as cross-reactive with unfolded or denatured A and D SnRNP polypeptides. Koren, et al., J. Immunol. 154:4857-4864 (1995), reported that murine and human antibodies to native DNA that cross-react with the A and D SnRNP polypeptides cause direct injury of cultured kidney cells. However, many questions remain about the mechanisms of lupus nephritis and the role of antibodies to dsDNA.
It is therefore an object of the present invention to provide methods and reagents for neutralizing the pathogenicity of antibodies to double stranded (ds) DNA.
It is another object of the present invention to develop specific therapy based on anti-idiotypes to anti-dsDNA.
Treatments have been developed for lupus patients using either anti-ID antibodies to dsDNA to block anti-dsDNA antibodies and/or kill the B cells producing the anti-dsDNA antibodies or ribosomal protein S1 peptides immunoreactive with anti-dsDNA antibodies. Examples demonstrate that (1) anti-dsDNA antibodies are cross-reactive with ribosomal protein S1, (2) anti-dsDNA antibodies suppress protein synthesis, presumably through inhibition of mRNA translation initiation, and (3) a normal human sera contains an anti-idiotypic antibody (anti-Id) to anti-dsDNA antibodies isolated from SLE patients which blocked the interactions between the anti-Id antibody fragment (Fab2) and various anti-dsDNA preparations.